Resveratrol (trans- or (E)-3,5,4′-trihydroxystilbene (1)) (FIG. 1) is a phytoalexin produced in plants and popularized as a beneficial ingredient of red wine. Resveratrol, its cis- or (Z)-isomer (2), and another stilbene derivative, pterostilbene (3), exhibit some anti-cancer activity. (FIG. 1) Recently, we found that resveratrol and pterostilbene, a stilbene found in blueberries, inhibit colon cancer cells at least partially through inhibiting Wnt/β-catenin signaling. Zhang, W. et al., J Med Chem 2011, 54, 1288-97.
Wnt/β-catenin signaling plays an important role in development and tumorigenesis, and the deregulation of Wnt signaling results in formation of tumors. Over 90% of colorectal cancers contain a mutation in APC or β-catenin, and these mutations stabilize β-catenin and activate Wnt signaling. Cells containing these mutations constitutively activate Wnt signaling and undergo strong proliferation that ultimately leads to cancer. Intercepting and blocking the Wnt/β-catenin pathway at various points in the signaling cascade is an attractive target for colon cancer chemoprevention and therapeutics.
Several Wnt inhibitors have been identified that target the upstream signaling of β-catenin and promote β-catenin degradation. Although these agents inhibit Wnt signaling in normal cells and some APC-mutated colon cancer cells, they may not be effective in colon cancer cells containing β-catenin mutations. Several other Wnt inhibitors have also been reported. However, side effects limit their potential use in humans. Natural products found in foods are potentially ideal chemopreventive and therapeutic agents for cancer if they possess sufficient potency and minimal toxicity.
Therefore, there is an ongoing need for compounds that are more potent than resveratrol and pterostilbene and that can be used to treat cancer and other ailments. There is also a particular need for compounds that do not exhibit deleterious side effects.